Background. New treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralizing antibody responses to past strains in influenza-infected subjects. The effect of Flu- IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear. Methods. We studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fcγ receptors and mediate antibody-dependent cellular cytotoxicity in vitro. The effect of Flu-IVIG infusion, compared to placebo infusion, was examined in serial plasma samples from 24 subjects with confirmed influenza infection in the INSIGHT FLU005 pilot study. Results. Flu-IVIG contains higher concentrations of Fc-functional antibodies than IVIG against a diverse range of influenza hemagglutinins. Following infusion of Flu-IVIG into influenza-infected subjects, a transient increase in Fc-functional antibodies was present for 1-3 days against infecting and noninfecting strains of influenza. Conclusions. Flu-IVIG contains antibodies with Fc-mediated functions against influenza virus, and passive transfer of Flu- IVIG increases anti-influenza Fc-functional antibodies in the plasma of influenza-infected subjects. Enhancement of Fc-functional antibodies to a diverse range of influenza strains suggests that Flu-IVIG infusion could prove useful in the context of novel influenza virus infections, when there may be minimal or no neutralizing antibodies in the Flu-IVIG preparation.
Bibliographical noteFunding Information:
Financial support. This work was supported by the Australian National Health and Medical Research Council (award number 1052979 to S. J. K.) and the NIAID Intramural Research Program and the NIAID Division of Clinical Research, through a contract with the University of Minnesota (Leidos prime contract HHSN261200800001E).
The Flu-IVIG studied was manufactured by Emergent BioSolutions under contract to the National Institutes of Health. The lot of Flu-IVIG used in the INSIGHT FLU005 pilot study was prepared in 2013 and had reciprocal geometric mean HAI antibody titers of 1:640 against the A/ California/7/2009(H1N1) pandemic influenza virus, 1:320 against the A/Victoria/361/2011(H3N2) influenza virus, and 1:160 against the B/Massachusetts/2/2012 influenza virus (see  for further details). We studied both the Flu-IVIG administered in the pilot study (prepared in 2013) and 3 additional, separately manufactured Flu-IVIG preparations (from 2014, 2015, and 2016, designated Flu-IVIG batches 1, 2, and 3 respectively) being used in an ongoing expanded clinical trial (INSIGHT FLU006, ClinicalTrials.gov identifier NCT02287467). Standard IVIGs manufactured in 2008 (prior to the 2009 pH1N1 pandemic), 2010, and 2016 were studied as comparators, with each containing pooled IgG from thousands of human immunodeficiency virus–negative donors. The IVIG prepared in 2016 is Intragam P (Seqirus Ltd) and we studied 3 additional batches of Intragam P (designated Intragam P batches 1–3). We also compared the Flu-IVIG from 2013, which was administered in the INSIGHT FLU005 pilot study, to a standard IVIG (Hizentra) also manufactured in 2013.
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.
- Fc receptor
- passive transfer